SUMMARY Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular obliteration, right heart failure and death. Despite several approved therapies, none are curative or address the primary molecular drivers of this highly morbid disease. Work by our group and others has highlighted the role of metabolic dysregulation such as mitochondrial dysfunction, insulin resistance and cardiac lipotoxicity in PAH. During the first term of our program project grant, we have published that glucose intolerance is common in human PAH and impacts survival. We have also assessed the effects of insulin-mediated mitochondrial lipid metabolism on the right ventricle (RV) and demonstrated that lipid deposition may be a key feature of RV dysfunction in PAH. Important questions remain: do interventions against insulin resistance improve PAH? Are there specific patients most likely to benefit from interventions against insulin resistance? Drug therapy, e.g. metformin, and exercise are the major currently practical interventions against insulin resistance in PAH. We initiated a pilot study of metformin in PAH patients in the first period of this grant with endpoints of safety, effect on plasma markers of oxidant stress and RV lipid deposition. We have enrolled nearly half of our target with no safety concerns. In preliminary analyses we have found that metformin in PAH may reduce RV lipid content and change plasma amino acid levels indicative of increased nitric oxide production. We and others have published that PAH patients are highly sedentary with reduced skeletal muscle function, suggesting that activity may be a modifiable feature of PAH. Exercise is known to be safe in PAH, but implementation in the US is limited by access to care. Our group recently showed that linking activity monitoring, e.g. fitbit, with automated, personalized text prompts to encourage activity led to a 300% increase in step counts. This approach may provide an innovative, inexpensive mechanism to increase activity in PAH, and thereby reduce insulin resistance. The mechanisms by which these insulin-sensitizing interventions may improve 6MWD and outcomes in PAH is unknown, however. Our preliminary data suggests metformin may reduce RV lipid content, which may affect the primary cause of death in PAH, RV failure. We now propose to test the hypothesis that interventions to improve insulin resistance will improve exercise capacity and functional class in PAH. We propose three specific aims to test this 1) A prospective 2x2 factorial design 12-week clinical trial of metformin or placebo and activity intervention or usual care to assess effect on six minute walk and functional class, 2) Assessment of the interventions in Aim 1 on RV and peripheral muscle function and lipid content and markers of pulmonary vascular disease to define how these interventions may work in PAH and 3) Identify and prospectively test peripheral blood markers of metformin response in PAH. The broad goals of this work are to demonstrate the efficacy and mechanisms of interventions against insulin resistance in PAH and to identify which patients are most likely to benefit from these interventions, moving to precision medicine in PAH.